Prenylation is carried out by cytoplasmic enzymes known as geranylgeranyltransferases and farnesyltransferases that covalently attach 20-carbon (geranylgeranyl) or 15-carbon (farnesyl) isoprenoids to the C-terminus of intracellular proteins via thioether linkages. Many proteins in signal transduction pathways are prenylated. Perhaps the best-characterized farnesylation products are the Ras ATPases. Mutated or oncogenic forms of Ras require farnesylation for their ability to transform cells. Several types of FTase inhibitors have been designed for use as potential anticancer agents ...

Glycoprotein Processing and Trafficking Inhibitors

N- and O-glycan structures contribute significantly to biological recognition and cell adhesion during immune surveillance, inflammatory reactions, hormone action, and viral infections. N-glycans are also observed on cells undergoing oncogenic transformation. Inhibitors of glycoprotein processing act late in the N-glycan processing pathway and block the oncogene-induced changes in cell surface oligosaccharide structures. The various processing inhibitors provide useful tools to understand the role of specific kinds of oligosaccharide structures in the function of various glycoproteins ...

3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors

HMG-CoA reductase catalyzes the 4-electron reduction of HMG-CoA to CoA and mevalonate, with oxidation of two molecules of NADPH. Regulation of the expression of hepatic HMG-CoA reductase is critical in maintaining normal cholesterol levels in serum and tissues. HMG-CoA reductase inhibitors (statins) are competitive inhibitors of this enzyme and have hypocholesterolemic properties. These inhibitors have close resemblance to HMG-CoA. During cholesterol biosynthesis they competitively inhibit the conversion of HMG-CoA to mevalonate, thereby reducing cholesterol biosynthesis in hepatic cells ...

NF-κB Activation Inhibitors

NF-κB, a eukaryotic transcription factor plays an important role in inflammation, autoimmune response, cell proliferation, and apoptosis by regulating the expression of genes involved in these processes. It consists of homo- or heterodimers of different subunits, which belong to a family of Rel/NF-κB proteins. NF-κB has been considered as a desirable target for therapy in various inflammatory diseases. In most cancer cells, NF-κB is constitutively active and resides in the nucleus. Designing antitumor inhibitors to block NF-κB activity or to increase sensitivity to conventional chemotherapy may have great therapeutic value ...

Protein Synthesis Inhibitors

Many inhibitors used to block protein synthesis are either antibiotics or toxins. Their mechanism of action includes the interruption of peptide-chain elongation, blocking the A site of ribosomes, and misreading of the genetic code. Some of them may also prevent the attachment of oligosaccharide side chains to glycoproteins ...

Sonic Hedgehog Signaling Inhibitors

Mammalian Hedgehog proteins include Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh). Shh, a secreted morphogen, has been implicated in several embryonic developmental processes It displays inductive, proliferative, neurotrophic, and neuroprotective properties. Shh functions with other signaling molecules such as the fibroblast growth factors and bone morphogenetic protein to mediate developmental processes. Mutations in any of the components of the Shh pathway can lead to congenital defects and diseases, including cancer. Hence, the Shh pathway has become a potential target for inhibitor/drug development for the treatment of cancers and degenerative diseases ...